The actions of melanin-concentrating hormone (MCH) are thought to be involved in anxiety, depression, obesity, and obesity-related disorders. MCH has been found to be a major regulator of eating behaviour and energy homeostasis and is the natural ligand for is the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). SLC-1 is sequentially homologous to the somatostatin receptors, and is frequently referred to as the “melanin-concentrating hormone receptor” (MCH receptor type 1, MCH1 receptor, or MCHR1).
In mice lacking the MCH1 receptor, there is no increased feeding response to MCH, and a lean phenotype is seen, suggesting that this receptor is responsible for mediating the feeding effect of MCH. MCH receptor antagonists have also been shown to block the feeding effects of MCH, and to reduce body weight & adiposity in diet-induced obese mice. The conservation of distribution and sequence of MCH1 receptors suggest a similar role for this receptor in man and rodent species. Hence, MCH receptor antagonists have been proposed as a treatment for obesity and other disorders characterised by excessive eating and body weight.
Emerging evidence also suggests that MCHR1 plays a role in the regulation of mood and stress. Within the central nervous system, MCHR1 mRNA and protein are distributed in various hypothalamic nuclei including, for example, the paraventricular nucleus (PVN) and the nucleus accumbens shell; and limbic structures including, for example, the hippocampus, septum, amygdala, locus coeruleus and dorsal raphe nucleus, all of which are thought to be involved in the regulation of emotion and stress.
Introduction of MCH into the medial preoptic area has been reported to induce anxiety, although contrary anxiolytic-like effects of MCH injection have also been reported. Injection of MCH into the nucleus accumbens shell, in which MCHR1 is abundant, decreased mobility in a forced swim test in rats, suggesting a depressive effect. Also, it has been reported that MCHR1 antagonists exhibited antidepressant and anxiolytic-like effects in rodent tests, suggesting a role for MCHR1 in depression and anxiety.
MCH antagonists are thus thought likely to provide benefit to numerous people and to have a potential to alleviate anxiety and depression and be useful for treating obesity and to obesity-related conditions.
MCH receptor antagonists having a bicyclic central core are disclosed in WO2006/066173 (benzothiazole or benzoxazole central core) and US2005/0222161 (benzimidazole core).
Our co-pending application WO 2010/0125390 discloses a compound of formula I
or a pharmaceutically acceptable salt thereof in whichR1 represents H, fluoro, chloro, bromo, cyano, a C1-3alkyl group optionally substituted by one or more fluoro, or a C1-2alkoxy group optionally substituted by one or more fluoro;A represents O or S;R2 and R3 independently represent H, fluoro, chloro, bromo, a C1-4alkyl group optionally substituted by one or more fluoro, or a C1-4alkoxy group optionally substituted by one or more fluoro; provided that R2 and R3 are not located meta to each other;R4 and R5 independently represent H or a C1-4alkyl group; andX and Y independently represent O or CH2 with the proviso that X and Y are different; and the use of such compounds in the treatment of a melanin-concentrating hormone related disease or condition for example obesity, obesity-related conditions, anxiety and depression.